Abstract: TH-PO332

Superiority of Mesenchymal Stem Cell-Derived Exosomes versus Parent Cells for Rescue Therapy of Advanced Stage AKI

Session Information

Category: Acute Kidney Injury

  • 002 AKI: Repair and Regeneration

Authors

  • Gooch, Anna, University of Utah and VA Medical Centers, Salt Lake City, Utah, United States
  • Zhang, Ping, University of Utah and VA Medical Centers, Salt Lake City, Utah, United States
  • Hu, Zhuma, University of Utah and VA Medical Centers, Salt Lake City, Utah, United States
  • Westenfelder, Christof, University of Utah and VA Medical Centers, Salt Lake City, Utah, United States
Background

Bone marrow and Adipose-derived Mesenchymal Stem Cells (MSCs and ASCs) have proven both pre-clinically and clinically to be effective for prevention of Acute Kidney Injury (AKI). Yet studies in which MSCs are given 48 hrs. post-insult, a time at which most patients with severe AKI are diagnosed and when no rescue therapy is available, show them to be ineffective or potentially damaging due to compromised renal blood flow, where introduction of large cells (~50µm) causes further deterioration of renal function. ASCs’ paracrine actions, including release of exosomes, are largely responsible for their protective effects, and others have shown that administration of ASC-derived exosomes can prevent AKI. Thus, we hypothesized that ASC-derived exosomes (40-150 nm), which can easily move through the microvasculature, may be effective rescue therapy for late stage AKI. Accordingly, we compared the therapeutic efficacy of ASC-derived exosomes vs. ASCs given late to rats with severe, non-spontaneously recovering AKI.

Methods

ASCs were isolated from Sprague Dawley (SD) rats and characterized by standard protocols. Exosomes were isolated from cultured ASCs using the ExoQuick TC kit (SBI), quantified (Nanosight and Bradford assay), and characterized by FACS for CD44 and CD29 surface protein expression. Adult, female SD rats were subjected to I/R AKI (52 min bilateral renal pedicle clamp). Serum Creatinine (SCr) was assessed at baseline, Days (D) 1, 2 and 3. If the SCr value on D2 was greater than that on D1, rats were treated via left carotid artery with either 1 ml of 1) 1x10e6 SD MSCs, 2) 200 ug protein-equivalent of SD MSC-derived exosomes (~4x10e10 exosomes), or 3) vehicle (1xPBS).

Results

SCr increased between D1 and D2 in all rats 1.6 ± 0.35 mg/dL (mean ± SD). As hypothesized, exosome administration on D2 caused a significant -1.7 ± 0.34 mg/dL drop in SCr by D3 vs. vehicle (+0.4 ± 1.1 mg/dL), while ASC administration did not, and in 25% of animals caused further functional deterioration.

Conclusion

Exosome therapy 2 days post-insult is superior to ASC therapy for rescue of AKI. Further optimization of the exosome therapy is expected to identify optimal treatment doses for advanced AKI.

Funding

  • Veterans Affairs Support